Fig. 3

Schematic diagram of the pathogenesis of hemophagocytic lymphohistiocytosis (HLH). The impaired ability of natural killer cells and cytotoxic T cells to secrete perforin and granzyme results in defective clearance of target cells, leading to sustained immune cell activation and excessive production of cytokines such as interleukin-1 (IL-1), IL-6, IL-18, and tumor necrosis factor-α (TNF-α). The intense pro-inflammatory response mediated by macrophages may also be due to increased production of autoantibodies and immune complexes, resulting in abnormal immune system activation and subsequently persistent inflammatory reactions. Infections, malignancies, and immune checkpoint inhibitors can also lead to excessive immune system activation, causing hyperactivity of macrophages and T cells, which release large amounts of pro-inflammatory cytokines, resulting in a cytokine storm